内科学
内分泌学
血管生成
PI3K/AKT/mTOR通路
瘦素
小鼠苗条素受体
生物
压力过载
自噬
蛋白激酶B
内皮
磷酸化
医学
信号转导
肌肉肥大
细胞生物学
细胞凋亡
肥胖
生物化学
心肌肥大
作者
Rajinikanth Gogiraju,Astrid Hubert,Jörg Fahrer,Beate K. Straub,Moritz Brandt,Philip Wenzel,Thomas Münzel,Stavros Konstantinides,Gerd Hasenfuß,Katrin Schäfer
出处
期刊:Circulation-heart Failure
[Ovid Technologies (Wolters Kluwer)]
日期:2019-01-01
卷期号:12 (1)
被引量:36
标识
DOI:10.1161/circheartfailure.118.005622
摘要
Background: Cardiac remodeling is modulated by overnutrition or starvation. The adipokine leptin mediates energy balance between adipose tissue and brain. Leptin and its receptors are expressed in the heart. Methods and Results: To examine the importance of endothelial leptin signaling in cardiac hypertrophy, transverse aortic constriction was used in mice with inducible endothelium-specific deletion of leptin receptors (End.LepR-KO) or littermate controls (End.LepR-WT). End.LepR-KO was associated with improved left ventricular function (fractional shortening, 28.4% versus 18.8%; P =0.0114), reduced left ventricular dilation (end-systolic inner left ventricular diameter, 3.59 versus 4.08 mm; P =0.0188) and lower heart weight (133 versus 173 mg; P <0.0001) 20 weeks after transverse aortic constriction. Histology and quantitative polymerase chain reaction analysis confirmed reduced cardiomyocyte hypertrophy. STAT3 (signal transducer and activator of transcription) activation was reduced, and Akt (protein kinase B) and mTOR (mammalian target of rapamycin) phosphorylation after transverse aortic constriction were blunted in End.LepR-KO hearts. Elevated LC3 (microtubule associated protein 1 light chain 3)-I/-II conversion ( P =0.0041) and increased (LC3II-positive) endothelial cells ( P =0.0042) in banded hearts of End.LepR-KO mice suggested improved cardiac angiogenesis because of activated autophagy. Microscopy confirmed autophagosome accumulation after genetic or small interfering RNA-mediated LepR downregulation. Enhanced sprouting angiogenesis was observed in endothelial cells ( P <0.0001) and aortic rings ( P =0.0060) from End.LepR-KO mice, and murine and human endothelial sprouting angiogenesis was reduced after mTOR inhibition using rapamycin or autophagy inhibition using 3-methyladenine. Banded End.LepR-KO mouse hearts exhibited less apoptosis ( P =0.0218), inflammation ( P =0.0251), and fibrosis ( P =0.0256). Reduced endothelial autophagy was also observed in myocardial biopsies of heart failure patients with cardiac fibrosis. Conclusions: Our findings suggest that endothelial leptin signaling contributes to cardiac fibrosis and functional deterioration by suppressing endothelial autophagy and promoting endothelial dysfunction in a chronic pressure overload model.
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